Systemic Sclerosis Diagnosis & Treatment Guide
Understand the diagnosis and treatment of Systemic sclerosis, including tests, medications,
Systemic Sclerosis (SSc)
Systemic Sclerosis (SSc) is a systemic autoimmune rheumatic disease. SSc is characterised by excess production and accumulation of collagen, in the skin and internal organs and by injuries to small arteries.
The pathogenesis of this disease is not fully understood.
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Systemic Sclerosis Diagnostic Methods
At every visit, patients with systemic sclerosis should undergo a thorough physical examination to assess involvement of different organs. Regular blood pressure monitoring, both at the clinic and at home, is especially important in patients with diffuse cutaneous SSc or new or worsening hypertension, as this may indicate the development of scleroderma renal crisis.
Autoantibody Tests
Autoantibodies play a key role in diagnosing systemic sclerosis and predicting disease type and outcome. Antinuclear antibodies (ANA) are positive in over 90% of cases, and if ANA is negative, other diagnoses should be considered. More specific autoantibodies, present in 60–70% of patients, provide additional diagnostic value and may appear months to years before clinical symptoms develop.
Anti-centromere antibody
Anti-centromere antibodies target centromere proteins (CENP-A, B, C, and D) and are most commonly found in limited cutaneous systemic sclerosis, though they may rarely appear in diffuse forms. They can also be seen in Sjögren syndrome and systemic lupus erythematosus. These antibodies are associated with an increased risk of pulmonary arterial hypertension (PAH), limited skin involvement, a lower risk of interstitial lung disease, and generally better survival compared to other systemic sclerosis–related autoantibodies.
Anti-topoisomerase I (Scl-70) antibody
Anti-topoisomerase I (Scl-70) antibodies are mainly seen in diffuse cutaneous systemic sclerosis and are rare in limited forms. Their presence is associated with a higher risk of extensive skin involvement, interstitial lung disease, and cardiac complications.
Anti-RNA polymerase III antibody
Anti-RNA polymerase III antibodies are mainly associated with diffuse cutaneous systemic sclerosis. They are linked to rapidly progressive and aggressive skin involvement, poorer skin outcomes, and an increased risk of scleroderma renal crisis. However, they are associated with a lower risk of interstitial lung disease and pulmonary arterial hypertension.
Anti–U3-RNP (fibrillarin) antibody
Anti-U3-RNP (fibrillarin) antibodies are more commonly seen in African American patients and are associated with a poorer prognosis in systemic sclerosis. They are linked to diffuse skin involvement and a higher risk of serious internal organ complications, including interstitial lung disease, pulmonary arterial hypertension, scleroderma renal crisis, muscle involvement, and cardiac problems.
Other autoantibodies
Other autoantibodies in systemic sclerosis include anti-Th/To antibodies, which are linked to limited skin involvement. Anti–PM/Scl antibodies are associated with limited cutaneous disease and overlap syndromes and increase the risk of inflammatory myositis and interstitial lung disease.
Anti–U1-RNP antibodies, more common in African Americans, are linked to overlap syndrome and mixed connective tissue disease, and are associated with limited skin involvement as well as a higher risk of inflammatory arthritis, myositis, lupus-related skin rashes, and lupus nephritis.
Anti-Ku antibodies are also seen in overlap syndromes and are associated with increased inflammatory arthritis and muscle involvement.
X-ray – detect calcinosis, loss of distal phalanges (acro-osteolysis), periarticular osteopenia; erosions are rare.
Musculoskeletal Ultrasound – Detect Tenosynovitis.
Electromyography (EMG) / Nerve Conduction Study – Detects muscle involvement (myopathy).
Muscle Biopsy – Confirms inflammatory myositis if EMG is abnormal.
High-Resolution CT (HRCT) Chest – Detects interstitial lung disease (early fibrosis, ground-glass changes).
Pulmonary Function Tests (Spirometry, Lung Volumes, DLCO) – Restrictive pattern and reduced diffusion capacity in ILD.
Transthoracic Echocardiography (TTE) – Suggests pulmonary arterial hypertension (PAH); visualizes pericardial effusion.
Right Heart Catheterization – Confirms PAH.
Electrocardiography (ECG) / Holter Monitoring – Detects arrhythmias.
Cardiac MRI – Identifies myocardial involvement and fibrosis.
Upper GI Endoscopy – Assesses esophageal and gastric involvement.
Esophageal Manometry – Detects esophageal dysmotility.
Barium Swallow Study – Shows dilated esophagus and impaired motility.
24-hour pH Monitoring – Detects gastroesophageal reflux.
CT scan (Chest) – Dilated, air-filled esophagus suggestive of esophageal dysmotility.
Systemic Sclerosis Treatment
Treatment of systemic sclerosis is not standardized and must be individualized. Management should be comprehensive, including patient and family education, medications, and rehabilitation.
Therapy decisions depend on disease type, duration, organ involvement, and the risks and benefits of treatment. Care of specific organ complications and a multidisciplinary approach involving various medical specialists are essential.
Mycophenolate mofetil (MMF) and cyclophosphamide (CYC) are commonly used as first-line therapies in systemic sclerosis.
Methotrexate is also recommended as first-line treatment for cutaneous involvement.
Cyclophosphamide can significantly reduce skin thickening and also improve interstitial lung disease (ILD) in affected patients.
Mycophenolate mofetil (MMF) improves skin sclerosis in systemic sclerosis. In patients with interstitial lung disease (ILD), 24 months of MMF treatment has shown significant clinical improvement. Additionally, MMF is generally better tolerated and has a more favorable safety profile compared to cyclophosphamide (CYC).
Hematopoietic stem cell transplantation (HSCT) is reserved for selected patients with rapidly progressive diffuse cutaneous systemic sclerosis and significant organ involvement who do not respond to standard immunosuppressive therapy and who do not have major cardiovascular complications. HSCT can slow the progression of organ damage, reduce skin thickening, and may improve interstitial lung disease (ILD) in appropriate candidates.
Organ-specific therapy is the most characteristic aspect of systemic sclerosis treatment. The goal is to protect affected organs, begin treatment of pathological changes as early as possible, and tailor management to the individual patient’s clinical presentation.
Organ-specific treatment in systemic sclerosis includes managing Raynaud’s phenomenon, digital ulcers, and necrosis with dihydropyridine calcium channel blockers, phosphodiesterase type 5 inhibitors, fluoxetine, or iloprost. Scleroderma renal crisis (SRC) requires prompt treatment with ACE inhibitors.
Interstitial lung disease (ILD) is treated with immunosuppressive therapy such as cyclophosphamide (CYC) or mycophenolate mofetil (MMF). Glucocorticoids may be used in ILD but should be given cautiously and in low doses due to the risk of triggering renal crisis.
The progression of lung involvement in systemic sclerosis–associated interstitial lung disease (SSc-ILD) can also be slowed by antifibrotic agents such as Pirfenidone and Nintedanib, which have been approved by the U.S. Food and Drug Administration for this indication.
In addition, in selected patients particularly those with early diffuse cutaneous systemic sclerosis (dcSSc) and inflammatory lung features, the monoclonal antibody Tocilizumab, which targets the interleukin-6 (IL-6) receptor, may offer therapeutic benefit.
In systemic sclerosis–associated pulmonary arterial hypertension (PAH), standard treatment traditionally involved monotherapy with prostacyclins, phosphodiesterase type 5 (PDE-5) inhibitors, or endothelin receptor antagonists. However, more recent evidence suggests that combination therapy—particularly with Tadalafil and Ambrisentan—may be a more effective strategy in improving outcomes for patients with PAH.
In patients with pulmonary arterial hypertension (PAH) in SSc, the standard of care was monotherapy with prostacyclins, phosphodiesterase inhibitors, and endothelin receptor antagonists, but recent literature suggest that combining tadalafil and ambrisentan is also a promising therapeutic strategy in PAH.
An observational study showed that combining Rituximab (a B-cell–depleting agent) with mycophenolate mofetil (MMF) is relatively safe and results in significant improvement in the modified Rodnan Skin Score (mRSS). Rituximab may also have disease-modifying effects in interstitial lung disease (ILD) associated with systemic sclerosis and has demonstrated greater improvement in skin scores compared with cyclophosphamide (CYC).
These findings suggest that rituximab may be a valuable treatment option for patients with skin and lung involvement who do not respond adequately to conventional immunosuppressive therapies.
There is growing interest in biological DMARDs (disease-modifying anti-rheumatic drugs) and small-molecule therapies for systemic sclerosis. Targeting inflammatory cytokines with agents such as Rituximab, Tocilizumab, and Abatacept, as well as treatment strategies guided by autoantibody profiles and skin gene expression, may offer new therapeutic options and advance the management of SSc.
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